Fetal Cardiology Featured Articles of May 2015

1. Global genetic analysis in mice unveils central role for cilia in congenital heart disease.

Li Y, Klena NT, Gabriel GC, Liu X, Kim AJ, Lemke K, Chen Y, Chatterjee B, Devine W, Damerla RR, Chang C, Yagi H, San Agustin JT, Thahir M, Anderton S, Lawhead C, Vescovi A, Pratt H, Morgan J, Haynes L, Smith CL, Eppig JT, Reinholdt L, Francis R, Leatherbury L, Ganapathiraju MK, Tobita K, Pazour GJ, Lo CW.

Nature. 2015 May 28;521(7553):520-4. doi: 10.1038/nature14269. Epub 2015 Mar 25.

PMID: 25807483

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Abarbanell picture smallComment from Dr. Ginnie Abarbanell (Atlanta), section editor of Fetal Cardiology Journal Watch:  This is a study of genetically altered mice [InbredC57BL/6Jmice mutagenized with ethylnitrosourea(ENU)] bred to recover recessive coding mutations for the purpose of evaluating the presence of congenital heart disease (CHD) and related genes.  Fetal echocardiograms were done on 87,355 mice to identify fetal mice with CHD.   The CHD diagnoses were then confirmed using micro-computed tomography (CT)/ micro-magnetic resonance imaging (MRI), necropsy and histopathology.  218 CHD mouse models were recovered.  Whole-exome sequencing identified 91 recessive CHD mutations in 61 genes. This included 34 cilia-related genes, 16 genes involved in cilia-transduced cell signaling, and 10 genes regulating vesicular trafficking, a pathway important for ciliogenesis and cell signaling.  These findings suggest that cilia and cilia transduced cell signaling have an important role in pathogenesis of CHD.

Take home points:

  1. Cilia and cilia transduced cell signaling are important in the pathogenesis of CHD
  2. These researchers were able to obtain impressive ultrasound and CT/MRI images of the fetal mouse heart. See illustrations below.
  3. Cardiac genetics is complex and as more discoveries are made the details become more intricate. See diagram of gene networks below.

fetal 1.1

fetal 1.2

2. Fetal MRI Detects Early Alterations of Brain Development in Tetralogy of Fallot.

Schellen C, Schwartz E, Gruber GM, Mlczoch E, Weber M, Ulm B, Brugger PC, Langs G, Salzer-Muhar U, Prayer D, Kasprian G.

Am J Obstet Gynecol. 2015 May 22. pii: S0002-9378(15)00522-0. doi: 10.1016/j.ajog.2015.05.046. [Epub ahead of print]

PMID: 26008177

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Comment from Dr. Ginnie Abarbanell (Atlanta), section editor of Fetal Cardiology Journal Watch:  Fetal brain MRIs were done on fetuses (n=24) with a prenatal diagnosis of Tetralogy of Fallot (TOF) and compared to age-matched control fetuses (n=24). Fetal MRIs were performed on the TOF group at a median of 25 weeks gestation age.  Total brain volume, gray matter volume and subcortical brain volume were found to be decreased in those fetuses with TOF.  Interestingly, the intracranial and cerebellar volumes was not reduced in fetuses with TOF compared to controls.  These findings suggest that TOF impacts brain development at a very early stage.

Take home points:

  1. This fetal MRI study demonstrates early changes in the fetal brain with TOF. These finding are consistent with the hypothesis that neurodevelopmental deficits in children with congenital heart disease (CHD) are at least in part secondary to differences in fetal brain development.

fetal 2.1

 

fetal 2.2

3. Disparities in the Prenatal Detection of Critical Congenital Heart Disease.

Hill GD, Block JR, Tanem JB, Frommelt MA.

Prenat Diagn. 2015 May 19. doi: 10.1002/pd.4622. [Epub ahead of print]

PMID: 25989740

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Comment from Dr. Ginnie Abarbanell (Atlanta), section editor of Fetal Cardiology Journal Watch:  Several studies have demonstrated improved outcomes in infants in whom a prenatal diagnosis of congenital (CHD) was available prior to delivery to aid in  planning of delivery and postnatal care.  This study evaluated a cohort of 535 infants born between 2007 and 2013 with CHD.  The overall prenatal diagnosis rate was 61% and had improved from 44% in 2007 to 69% in 2013.  Risk factors identified with missed prenatal diagnosis were (1) a lesion that required a view other than a four chamber view to make the diagnosis, (2) absence of another organ system anomaly, and (3) living in a higher poverty or lower population density (rural) communities.  Prenatal detection rate was highest in tricuspid atresia and lowest in total anomalous pulmonary venous connection.  Researches found that “Lesions such as aortic stenosis, double outlet right ventricle, pulmonary atresia, tetralogy of Fallot, transposition of the great arteries, and truncus arteriosus, which require an outflow tract view, and coarctation of the aorta, interrupted aortic arch, and total anomalous pulmonary venous return, which require an aortic arch view or color and spectral Doppler imaging, were less commonly identified in rural communities.”  The authors conclude “Our data suggest that training programs in detection of CHD by screening obstetric ultrasound should be targeted to these impoverished, rural communities for the greatest impact.”

Take home points:

  1. Prenatal diagnosis of CHD has improved.
  2. There is still room for improvement with education regarding identification of CHD not classically seen on the 4 chamber cardiac view especially in more rural areas where maternal fetal medicine specialists are less prevalent.

fetal 3.1

fetal 3.2

 

4. The A1298C Methylenetetrahydrofolate Reductase Gene Variant as a Susceptibility Gene for Non-Syndromic Conotruncal Heart Defects in an Indian Population.

Koshy T, Venkatesan V, Perumal V, Hegde S, Paul SF.

Pediatr Cardiol. 2015 May 17. [Epub ahead of print]

PMID: 25981563

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Shaji Menon Portrait 12.15.14Comment from Dr. Shaji Menon (Salt Lake City, UT), section editor of Pediatric Cardiology Journal Watch: Conotruncal heart defects (CTHDs), accounts for 10–15 % of congenital heart diseases (CHD). This defects involve cardiac structures that are partially derived from cell lineages such as the cardiac neural crest cells and the secondary heart field. Prenatal use of folic acid has been reported to a reduced risk of CHDs and neural tube defects (NTD). Single nucleotide polymorphisms (SNPs) in the genes controlling folate metabolism has been associated with CHDs. Methylenetetrahydrofolate reductase (MTHFR), plays a central role in folate metabolism. The objective of this case-control study was to devaluate the association of six selected folate-metabolizing gene polymorphisms with the risk of non-syndromic CTHDs in an Indian population. The findings of this study shows that 5, 10-methylenetetrahydrofolate (MTHFR) A1298C polymorphism, the CC variant homozygote genotype was associated with a significantly increased risk of CTHDs in Indian population. This study builds on the existing evidence of role of folate metabolism in cardiovascular development and possibility of using folic acid supplementation in reducing the incidence of CHDs.

fetal 4.1

 

5. Prenatal diagnosis of giant cardiac rhabdomyoma in tuberous sclerosis complex: a new therapeutic option with everolimus.

Mlczoch E, Hanslik A, Luckner D, Kitzmüller E, Prayer D, Michel-Behnke I.

Ultrasound Obstet Gynecol. 2015 May;45(5):618-21. doi: 10.1002/uog.13434.

PMID: 24913039

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Comment from Dr. Shaji Menon (Salt Lake City, UT), section editor of Pediatric Cardiology Journal Watch: Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder characterized by abnormal cell proliferation and tumor growth in a number of organ systems, including brain, kidneys, skin, liver, eyes and heart. Causative mutations can occur in either the TSC1 gene on chromosome 9q34 (hamartin) or the TSC2 gene on chromosome 16p13.3 (tuberin). Mutations in these two genes can lead to up regulation of mTOR complex 1, resulting in abnormal cell proliferation, cell growth and protein synthesis. Cardiac rabdomyoma are often diagnosed prenatally and the rabdomyoma growth is mainly during the second and third trimesters, continuing until the early postnatal period, followed by regression during the first year of postnatal life. In majority, the standard of care is observation until spontaneous regression. However, in rare cases of large rabdomyomas causing hemodynamic compromise secondary to mechanical obstruction, surgical intervention may be required.  This case report describes rapid involution of a prenatally diagnosed giant rabdomyoma causing right ventricular outflow tract obstruction following postnatal treatment with the mTOR inhibitor everolimus. This report and similar previous reports provides us with a novel and promising therapeutic approaches with mTOR inhibitors in patients with TSC diagnosed with large cardiac rhabdomyomas.

fetal 4.2

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Fetal Cardiology articles of May 2015

  1. Developments in our understanding of the genetic basis of birth defects.

Webber DM, MacLeod SL, Bamshad MJ, Shaw GM, Finnell RH, Shete SS, Witte JS, Erickson SW, Murphy LD, Hobbs C.

Birth Defects Res A Clin Mol Teratol. 2015 May 28. doi: 10.1002/bdra.23385. [Epub ahead of print]

PMID: 26033863

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  1. Global genetic analysis in mice unveils central role for cilia in congenital heart disease.

Li Y, Klena NT, Gabriel GC, Liu X, Kim AJ, Lemke K, Chen Y, Chatterjee B, Devine W, Damerla RR, Chang C, Yagi H, San Agustin JT, Thahir M, Anderton S, Lawhead C, Vescovi A, Pratt H, Morgan J, Haynes L, Smith CL, Eppig JT, Reinholdt L, Francis R, Leatherbury L, Ganapathiraju MK, Tobita K, Pazour GJ, Lo CW.

Nature. 2015 May 28;521(7553):520-4. doi: 10.1038/nature14269. Epub 2015 Mar 25.

PMID: 25807483

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  1. Cardiac disease modelling using Induced Pluripotent Stem Cells.

Yang C, Al-Aama J, Stojkovic M, Keavney B, Trafford A, Lako M, Armstrong L.

Stem Cells. 2015 May 28. doi: 10.1002/stem.2070. [Epub ahead of print]

PMID: 26033645

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  1. A systematic variant screening in familial cases of congenital heart defects demonstrates the usefulness of molecular genetics in this field.

El Malti R, Liu H, Doray B, Thauvin C, Maltret A, Dauphin C, Gonçalves-Rocha M, Teboul M, Blanchet P, Roume J, Gronier C, Ducreux C, Veyrier M, Marçon F, Acar P, Lusson JR, Levy M, Beyler C, Vigneron J, Cordier-Alex MP, Heitz F, Sanlaville D, Bonnet D, Bouvagnet P.

Eur J Hum Genet. 2015 May 27. doi: 10.1038/ejhg.2015.105. [Epub ahead of print]

PMID: 26014430

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  1. Fetal MRI Detects Early Alterations of Brain Development in Tetralogy of Fallot.

Schellen C, Schwartz E, Gruber GM, Mlczoch E, Weber M, Ulm B, Brugger PC, Langs G, Salzer-Muhar U, Prayer D, Kasprian G.

Am J Obstet Gynecol. 2015 May 22. pii: S0002-9378(15)00522-0. doi: 10.1016/j.ajog.2015.05.046. [Epub ahead of print]

PMID: 26008177

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  1. Functional Analysis of Two Novel Mutations in TWIST1 Protein Motifs Found in Ventricular Septal Defect Patients.

Deng X, Pan H, Wang J, Wang B, Cheng Z, Cheng L, Zhao L, Li H, Ma X.

Pediatr Cardiol. 2015 May 19. [Epub ahead of print]

PMID: 25981568

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  1. Disparities in the Prenatal Detection of Critical Congenital Heart Disease.

Hill GD, Block JR, Tanem JB, Frommelt MA.

Prenat Diagn. 2015 May 19. doi: 10.1002/pd.4622. [Epub ahead of print]

PMID: 25989740

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  1. Whole Genome Sequencing and Integrative Genomic Analysis Approach on Two 22q11.2 Deletion Syndrome Family Trios for Genotype to Phenotype Correlations.

Chung JH, Cai J, Suskin BG, Zhang Z, Coleman K, Morrow BE.

Hum Mutat. 2015 May 15. doi: 10.1002/humu.22814. [Epub ahead of print]

PMID: 25981510

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  1. The Impact of Oral Intake of Dydrogesterone on Fetal Heart Development During Early Pregnancy.

Zaqout M, Aslem E, Abuqamar M, Abughazza O, Panzer J, De Wolf D.

Pediatr Cardiol. 2015 May 15. [Epub ahead of print]

PMID: 25972284

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  1. Physiologically inspired cardiac scaffolds for tailored in vivo function and heart regeneration.

Kaiser NJ, Coulombe KL.

Biomed Mater. 2015 May 13;10(3):034003. doi: 10.1088/1748-6041/10/3/034003.

PMID: 25970645

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  1. A modified multiplex ligation-dependent probe amplification method for the detection of 22q11.2 copy number variations in patients with congenital heart disease.

Zhang X, Xu Y, Liu D, Geng J, Chen S, Jiang Z, Fu Q, Sun K.

BMC Genomics. 2015 May 8;16:364. doi: 10.1186/s12864-015-1590-5.

PMID: 25952753 Free PMC Article

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  1. Prenatal Diagnosis of a Persistent Fifth Aortic Arch, Pulmonary-to-Systemic type: An Unusual Association with Evolving Aortic Coarctation.

Bhatla P, Chakravarti S, Axel L, Ludomirsky A, Revah G.

Echocardiography. 2015 May;32(5):875-7. doi: 10.1111/echo.12850. Epub 2014 Nov 21.

PMID: 25418608

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  1. Autophagy: A potential link between Acquired von Willebrand syndrome and congenital heart disease.

Zhu Z, Fang Z, Hu X, Zhou S.

Int J Cardiol. 2015 May 1;186:37-8. doi: 10.1016/j.ijcard.2015.03.221. Epub 2015 Mar 18. No abstract available.

PMID: 25804464

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  1. Positional mapping of PRKD1, NRP1 and PRDM1 as novel candidate disease genes in truncus arteriosus.

Shaheen R, Al Hashem A, Alghamdi MH, Seidahmad MZ, Wakil SM, Dagriri K, Keavney B, Goodship J, Alyousif S, Al-Habshan FM, Alhussein K, Almoisheer A, Ibrahim N, Alkuraya FS.

J Med Genet. 2015 May;52(5):322-9. doi: 10.1136/jmedgenet-2015-102992. Epub 2015 Feb 23.

PMID: 25713110

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  1. Genetics of congenital heart disease: Beyond half-measures.

Barnett P, Postma AV.

Trends Cardiovasc Med. 2015 May;25(4):302-4. doi: 10.1016/j.tcm.2014.11.012. Epub 2014 Dec 4. No abstract available.

PMID: 25572011

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  1. Molecular insight into heart development and congenital heart disease: An update review from the Arab countries.

Aburawi EH, Aburawi HE, Bagnall KM, Bhuiyan ZA.

Trends Cardiovasc Med. 2015 May;25(4):291-301. doi: 10.1016/j.tcm.2014.11.007. Epub 2014 Nov 20. Review.

PMID: 25541328

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  1. Association of TGFBR2 rs6785358 Polymorphism with Increased Risk of Congenital Ventricular Septal Defect in a Chinese Population.

Li XT, Shen CQ, Zhang R, Shi JK, Li ZH, Liu HY, Sun B, Wang K, Yan LR.

Pediatr Cardiol. 2015 May 30. [Epub ahead of print]

PMID: 26022443

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  1. Fetal Ventricular Hypertrabeculation/Noncompaction: Clinical Presentation, Genetics, Associated Cardiac and Extracardiac Abnormalities and Outcome.

Stöllberger C, Wegner C, Finsterer J.

Pediatr Cardiol. 2015 May 27. [Epub ahead of print]

PMID: 26008764

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  1. The A1298C Methylenetetrahydrofolate Reductase Gene Variant as a Susceptibility Gene for Non-Syndromic Conotruncal Heart Defects in an Indian Population.

Koshy T, Venkatesan V, Perumal V, Hegde S, Paul SF.

Pediatr Cardiol. 2015 May 17. [Epub ahead of print]

PMID: 25981563

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  1. Prenatal diagnosis of aorto-left ventricular tunnel: introducing the ‘cockade sign’.

Christmann M, Dave H, Buechel EV.

Eur Heart J. 2015 May 7;36(18):1136. doi: 10.1093/eurheartj/ehu525. Epub 2015 Feb 2. No abstract available.

PMID: 25650394

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  1. MEIS2 involvement in cardiac development, cleft palate, and intellectual disability.

Louw JJ, Corveleyn A, Jia Y, Hens G, Gewillig M, Devriendt K.

Am J Med Genet A. 2015 May;167(5):1142-6. doi: 10.1002/ajmg.a.36989. Epub 2015 Feb 25.

PMID: 25712757

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  1. ERBB2 triggers mammalian heart regeneration by promoting cardiomyocyte dedifferentiation and proliferation.

D’Uva G, Aharonov A, Lauriola M, Kain D, Yahalom-Ronen Y, Carvalho S, Weisinger K, Bassat E, Rajchman D, Yifa O, Lysenko M, Konfino T, Hegesh J, Brenner O, Neeman M, Yarden Y, Leor J, Sarig R, Harvey RP, Tzahor E.

Nat Cell Biol. 2015 May;17(5):627-38. doi: 10.1038/ncb3149. Epub 2015 Apr 6.

PMID: 25848746

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  1. Prenatal diagnosis of giant cardiac rhabdomyoma in tuberous sclerosis complex: a new therapeutic option with everolimus.

Mlczoch E, Hanslik A, Luckner D, Kitzmüller E, Prayer D, Michel-Behnke I.

Ultrasound Obstet Gynecol. 2015 May;45(5):618-21. doi: 10.1002/uog.13434.

PMID: 24913039

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